Fighting Females: Neural and Behavioral Consequences of Social Defeat Stress in Female Mice.

BACKGROUND: Despite the twofold higher prevalence of major depressive and posttraumatic stress disorders in women compared with men, most clinical and preclinical studies have focused on male subjects. We used an ethological murine model to study several cardinal symptoms of affective disorders in the female targets of female aggression. METHODS: Intact Swiss Webster (CFW) female resident mice were housed with castrated male mice and tested for aggression toward female intruders. For 10 days, aggressive CFW female residents defeated C57BL/6J (B6) female intruders during 5-minute encounters. Measures of corticosterone, c-Fos activation in hypothalamic and limbic structures, and species-typical behaviors were collected from defeated and control females. Ketamine (20 mg/kg) was tested for its potential to reverse stress-induced social deficits. RESULTS: Housed with a castrated male mouse, most intact resident CFW females readily attacked unfamiliar B6 female intruders, inflicting >40 bites in a 5-minute encounter. Compared with controls, defeated B6 females exhibited elevated plasma corticosterone and increased c-Fos activation in the medial amygdala, ventral lateral septum, ventromedial hypothalamus, and hypothalamic paraventricular nucleus. Chronically defeated females also showed vigilance-like behavior and deficits in social interactions, novel object investigation, and nesting. The duration of social interactions increased 24 hours after chronically defeated female mice received a systemic dose of ketamine. CONCLUSIONS: These findings demonstrate that CFW female mice living with male conspecifics can be used as aggressive residents in an ethological model of female social defeat stress. These novel behavioral methods will encourage further studies of sex-specific neural, physiological, and behavioral adaptations to chronic stress and the biological bases for interfemale aggression.

Chronic high-dose creatine has opposing effects on depression-related gene expression and behavior in intact and sex hormone-treated gonadectomized male and female rats.

Creatine is an antioxidant, neuromodulator and key regulator of energy metabolism shown to improve depressive symptoms in humans and animals, especially in females. To better understand the pharmacological effects of creatine, we examined its influence on depression-related hippocampal gene expression and behaviors in the presence and absence of sex steroids. Sham-operated and gonadectomized male and female rats were fed chow alone or chow blended with either 2% or 4% w/w creatine monohydrate for five weeks before forced swim, open field, and wire suspension tests, or seven weeks total. Before supplementation, males were chronically implanted with an empty or a testosterone-filled (T) capsule (10-mm surface release), and females were administered progesterone (P, 250 µg), estradiol benzoate (EB, 2.5 µg), EB+P, or sesame oil vehicle weekly. Relative to non-supplemented shams, all hippocampal plasticity-related mRNAs measured, including brain-derived neurotrophic factor (BDNF), tyrosine kinase B, doublecortin, calretinin, and calbindin, were downregulated in sham males given 4% creatine, and BDNF, doublecortin, and calbindin mRNAs were downregulated in sham females given 4% creatine. In contrast, combined 4% creatine+T in castrates prevented downregulation of BDNF, doublecortin, and calretinin mRNAs. Similarly, combined 4% creatine+EB+P in ovariectomized females attenuated downregulation of BDNF and calbindin mRNA levels. Moderate antidepressant and anxiolytic-like behaviors were observed in EB+P-treated ovariectomized females fed creatine, with similar trends in T-treated castrates fed creatine. Altogether, these data show that chronic, high-dose creatine has opposing effects on neuroplasticity-related genes and depressive behavior in intact and gonadectomized male and female rats. The dose and schedule of creatine used negatively impacted hippocampal neuronal integrity in otherwise healthy brains, possibly through negative compensatory changes in energy metabolism, whereas combined creatine and sex steroids acted in a neuroprotective manner in gonadectomized rats, potentially by reducing metabolic complications associated with castration or ovariectomy.

Sex differences in behavioral and neural cross-sensitization and escalated cocaine taking as a result of episodic social defeat stress in rats.

RATIONALE: Episodic social defeat stress results in cross-sensitization to cocaine, characterized by augmentation of locomotor activity, dopamine (DA) levels in the nucleus accumbens (NAc), and cocaine self-administration during a 24-h "binge" in male rats. However, females are more vulnerable than males at each phase of cocaine addiction, and while these sex differences have been replicated in rats, the role of social stress in females remains largely neglected. OBJECTIVE: This study examined sex and estrous cycle differences in behavioral and dopaminergic cross-sensitization to cocaine, as well as cocaine taking in an unlimited-access self-administration "binge." METHODS: Long-Evans rats underwent episodic social defeat and were assessed 10 days later for either (1) behavioral sensitization, as determined by locomotor activity in response to acute cocaine (10 mg/kg, i.p.), (2) neural sensitization, as determined by in vivo microdialysis of DA in the NAc shell in response to acute cocaine, or (3) intravenous self-administration of cocaine (0.3 mg/kg/infusion) in an unlimited-access "binge." RESULTS: Social defeat stress resulted in behavioral and dopaminergic cross-sensitization in both sexes, but the effect was larger and longer lasting in stressed females. Furthermore, while stress engendered a longer "binge" in both sexes, females had a significantly longer "binge" duration than males. CONCLUSIONS: These data suggest that socially stressed females exhibit a larger and longer lasting behavioral and neural cross-sensitization, as well as more dysregulated cocaine taking, than males possibly due to different alterations in the dopaminergic response in the NAc. Furthermore, estrogens appear to play a facilitatory role in both behavioral and dopaminergic sensitization.

6-hydroxydopamine lesions enhance progesterone-facilitated lordosis of rats and hamsters, independent of effects on motor behavior.

The Ventral Tegmental Area (VTA) is an important brain area for progesterone (P(4))'s effects to facilitate female sexual behavior of rodents. We investigated the importance of dopaminergic neurons in the VTA, and two dopaminergic projection sites, the Nucleus Accumbens (NAc), and Caudate Nucleus of the Striatum (CN), in modulating P(4)-facilitated sex and motor behavior. Ovariectomized (ovx) rats and hamsters, administered estradiol benzoate (10 microg) and P(4) (0, 50, 100, 200, or 500 microg), were tested for motor behavior in a chamber that automatically records horizontal beam breaks, and for sexual behavior in response to a sexually-experienced male. Animals were tested once a week until each P(4) dosage was received; animals then had bilateral 6-hydroxydopamine (6-OHDA) or sham lesions to the VTA, NAc, or CN and were re-tested at each P(4) dosage on subsequent weeks. Fixed brains were stained with cresyl violet and processed for dopamine transporter (DAT) immunoreactivity. The number of cresyl violet stained cells was significantly lower in all 6-OHDA infusion sites compared to non-6-OHDA infusion sites of rats and hamsters. Also, in rats, the number of DAT-immunoreactive neurons was lower in all 6-OHDA infusion sites compared to non-6-OHDA infusion sites. In rats, 6-OHDA but not sham, lesions to the VTA, NAc, or CN produced P(4)-dependent increases in lordosis quotients and resulted in modest increases in motor behavior. In hamsters, 6-OHDA, but not sham, lesions to the VTA, NAc, or CN produced P(4)-dependent increases in total lordosis durations and produced modest decreases in motor behavior. This suggests that the dopaminergic output neurons of midbrain VTA may play an important role in modulation of P(4)-facilitated sexual lordosis among rodents.

MK-801 infusions to the ventral tegmental area and ventromedial hypothalamus produce opposite effects on lordosis of hormone-primed rats.

Progesterone initiates female sexual behavior of rodents (lordosis) through actions at intracellular progestin receptors in the ventromedial hypothalamus. Progesterone's metabolite, 5alpha-pregnan-3alpha-ol-20-one, mediates the intensity and duration of lordosis through its actions at GABA(A) receptors in the ventral tegmental area. Whether progestins can influence sexual behavior through actions that involve N-methyl-D-aspartate receptors (NMDARs) in the ventromedial hypothalamus and ventral tegmental area was investigated. The current study examines the effect of bilateral ventral tegmental area or ventromedial hypothalamus infusions of the non-competitive NMDAR antagonist (+)-MK-801 hydrogen maleate (MK-801; 0, 20, or 200 ng) on lordosis, motor activity, and NMDA R1 subtype (NMDAR1) immunoreactivity in estradiol benzoate (10 microg)+progesterone (50 microg)- and estradiol benzoate+vehicle primed rats. Compared to vehicle infusions, infusions of MK-801 to the ventral tegmental area facilitated lordosis of estradiol benzoate (10 microg)+progesterone (50 microg)- and estradiol benzoate+vehicle primed rats. Infusions of MK-801 to the ventromedial hypothalamus inhibited lordosis of estradiol benzoate (10 microg)+progesterone (50 microg)- and estradiol benzoate+vehicle primed rats, compared to vehicle. There was no effect of MK-801 infusions to the ventral tegmental area or the ventromedial hypothalamus on motor behavior. Immunocytochemistry for NMDAR1 revealed MK-801 (200 ng) infusions to the ventral tegmental area or ventromedial hypothalamus of estradiol benzoate (10 microg)+progesterone (50 microg)- or estradiol benzoate+vehicle primed rats significantly reduced the number of darkly stained NMDAR1-immunoreactive cells, compared to vehicle infusions. These data suggest NMDARs may be important in the mediation of hormonal actions in both the ventral tegmental area and the ventromedial hypothalamus for sexual receptivity of rodents, but in different ways.